5‐Aminoimidazole‐4‐carboxamide‐1‐β‐D‐ribofuranoside (AICA riboside) has been extensively used in vitro and in vivo to activate the AMP‐activated protein kinase (AMPK), a metabolic sensor involved in both cellular and whole body energy homeostasis. However, it has been recently highlighted that AICA riboside also exerts AMPK‐independent effects, mainly on AMP‐regulated enzymes and mitochondrial oxidative phosphorylation (OXPHOS), leading to the conclusion that new compounds with reduced off target effects are needed to specifically activate AMPK. Here, we review recent findings on newly discovered AMPK activators, notably on A‐769662, a nonnucleoside compound from the thienopyridone family. We also report that A‐769662 is able to activate AMPK and stimulate glucose uptake in both L6 cells and primary myotubes derived from human satellite cells. In addition, A‐769662 increases AMPK activity and phosphorylation of its main downstream targets in primary cultured rat hepatocytes but, by contrast with AICA riboside, does neither affect mitochondrial OXPHOS nor change cellular AMP:ATP ratio. We conclude that A‐769662 could be one of the new promising chemical agents to activate AMPK with limited AMPK‐independent side effects. © 2008 IUBMB IUBMB Life, 61(1): 18–26, 2009